Bicyclic pyrimidine derivatives

• US 7,524,852 B2
• Filed: 06/06/2003
• Issued: 04/28/2009
• Est. Priority Date: 06/07/2002
• Status: Expired due to Fees

• Current Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited)
• Original Assignee: Kyowa Hakko Kogyo Company Limited (Kirin Holdings Company Limited)
• Inventors: Sato, Takashi, Suzuki, Koji, Arai, Hitoshi, Ueno, Kimihisa, Miki, Ichiro, Iwase, Miho, Fujii, Shinya, Yanagawa, Koji, Nakanishi, Satoshi, Yamaura, Yosuke, Kawabe, Ari, Ohshima, Etsuo, Miyama, Motoki, Ishida, Hiroshi, Kobayashi, Katsuya, Matsumura, Tsutomu, Aratake, Seiji
• Primary Examiner(s): Berch; Mark L
• Assistant Examiner(s): Jaisle; Cecilia M
• Application Number:
  US10/516,750
• Publication Number:
  US 20070037834A1
• Time in Patent Office: 2,153 Days
• Field of Search: 544/279, 514/264.11
• US Class Current: 514/264.11
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 263/58 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

[wherein m and n may be the same or different and each represents an integer of 1 to 3 wherein m+n is 4 or less; R¹ represents —NR⁴R⁵ (wherein R⁴ and R⁵ may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl or the like); R² represents the above Formula (II), Formula (IV) or the like; A represents a single bond, —C(═O)—, —SO₂—, —OC(═O)— or the like; and R³ represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or the like]

Bicyclic pyrimidine derivatives represented by the above Formula (I), or quaternary ammonium salts thereof, or pharmaceutically acceptable salts thereof, or the like, are provided. These have anti-inflammatory activities or modulation activities on the functions of TARC and/or MDC and are useful for treating and/or preventing a disease which is related to T cells, such as an allergic disease, an autoimmune disease or transplant rejection.

Claims

1. A bicyclic pyrimidine represented by following Formula (I):

2. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a hydrogen atom;

and R⁵ is substituted or unsubstituted aralkyl.

3. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R⁴ is a hydrogen atom;

and R⁵ is substituted or unsubstituted cycloalkyl.

4. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to any of claims 1, 2, or 3, wherein s is 0.

5. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 4, wherein q is 1 or 2.

6. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein X^a is a hydrogen atom.

7. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 6, wherein R¹⁰ is —

NR^8AR^9A, a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heteroalicyclic group.

8. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or a substituted or unsubstituted heteroaromatic group.

9. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 4 and a pharmaceutically acceptable excipient.

10. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to any of claims 1, 2, or 3, wherein A is —

C(═

O)—

, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cyloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl.

11. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 4, wherein A is —

C(═

O)—

, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cyloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl.

12. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein A is —

C(═

O)—

, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cyloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl.

13. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein A is —

C(═

O)—

, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cyloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl.

14. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein A is —

C(═

O)—

, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cyloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl.

15. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to any of claims 1, 2, or 3, wherein A is —

C(═

O)—

, and R³ is —

NR^8BR^9B (wherein R^8B and R^9B have the same meaning as R⁸ and R⁹, respectively.

16. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 4, wherein A is —

C(═

O)—

, and R³ is —

NR^8BR^9B (wherein R^8B and R^9B have the same meaning as R⁸ and R⁹, respectively.

17. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein A is —

C(═

O)—

, and R³ is —

NR^8BR^9B (wherein R^8B and R^9B have the same meaning as R⁸ and R⁹, respectively.

18. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 6, wherein A is —

C(═

O)—

, and R³ is —

NR^8BR^9B (wherein R^8B and R^9B have the same meaning as R⁸ and R⁹, respectively.

19. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein A is —

C(═

O)—

, and R³ is —

NR^8BR^9B (wherein R^8B and R^9B have the same meaning as R⁸ and R⁹, respectively.

20. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to any of claims 1, 2, or 3, wherein A is —

SO₂, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted aryl.

21. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 4, wherein A is —

SO₂, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted aryl.

22. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 5, wherein A is —

SO₂, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted aryl.

23. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 6, wherein A is —

SO₂, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted aryl.

24. The bicyclic pyrimidine, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 7, wherein A is wherein A is —

SO₂, and R³ is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl or substituted or unsubstituted aryl.

25. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 10 and a pharmaceutical acceptable excipient.

26. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 11 and a pharmaceutical acceptable excipient.

27. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 12 and a pharmaceutical acceptable excipient.

28. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 13 and a pharmaceutical acceptable excipient.

29. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 14 and a pharmaceutical acceptable excipient.

30. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 15 and a pharmaceutical acceptable excipient.

31. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 16 and a pharmaceutical acceptable excipient.

32. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 17 and a pharmaceutical acceptable excipient.

33. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 18 and a pharmaceutical acceptable excipient.

34. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 19 and a pharmaceutical acceptable excipient.

35. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 20 and a pharmaceutical acceptable excipient.

36. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 21 and a pharmaceutical acceptable excipient.

37. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 22 and a pharmaceutical acceptable excipient.

38. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 23 and a pharmaceutical acceptable excipient.

39. A pharmaceutical composition which comprises, as an active ingredient, the bicyclic pyrimidine derivative, or the quaternary ammonium salt thereof, or the pharmaceutically acceptable salt thereof according to claim 24 and a pharmaceutical acceptable excipient.